Tag Archives: placebo

What’s the opposite of a placebo? An active drug, of course. But what’s the opposite of a placebo response? That would be a “nocebo” response, in which placebos produce adverse side effects.

“It’s somewhat hypothetical, but you can imagine that if somebody feels they will get better, they will get better, and if they feel that they’re taking something that’s not good for them, they might get worse,” according to Dr. Allan Krumholz, professor of neurology and director of the Maryland Epilepsy Center, Baltimore.

Image courtesy of Dr. Tricia Y. Ting

Pill color and appearance have been identified as a potential source of “nocebo” response, and differences in appearance between brand-name and generic drugs have been postulated to explain why some patients experience increased adverse events when they switch from brand-name to generics.

In response to this growing concern, in August 2010 the Food and Drug Administration solicited proposals for bioequivalence studies of the impact of switching from brand-name antiepileptic drug lamotrigine (Lamictal) to generic among patients with epilepsy in the outpatient setting.

This is a new way of conducting such trials. “Pharmacokinetics trials across all areas of medicine have traditionally been highly controlled single-dose studies in healthy volunteers dosed in the laboratory setting,” said lead investigator Dr. Tricia Y. Ting, a neurologist who works with Dr. Krumholz at the UMD epilepsy center.

Because the brand-name Lamictal and its generic counterparts look very different, the investigators decided to over-encapsulate the pills with identical coverings in order to “blind” the patients to which formulation they were taking.

But in order to do that, they first needed to determine whether the color of the pill would impact the patients’ perception of safety and efficacy. A group of 80 adult epilepsy patients were shown standard AA size capsules in five “global colors” (white, yellow, gray, caramel, maroon) and asked to select any color(s) considered “unacceptable” and to rank their preferences.

More patients deemed gray, caramel and maroon colors “unacceptable” (21%, 19%, and 20%, respectively) compared with the white and yellow (5% and 4%, respectively). There was a clear preference for white and yellow pills over the other, darker colors, without much difference between white and yellow.

But, there were patients who selected maroon as their “preferred” color. “Some people didn’t have any preference. Some had a very strong preference. One patient, an artist, liked the darker colors. It was different for different people,” noted Dr. Karen M. Aquino, a neurology fellow who worked on the nocebo study.

So what pill color will the bioequivalence study use? “To optimize drug adherence, white colored capsules will be used for over-encapsulation,” Dr. Ting wrote in her poster, which was presented at the American Epilepsy Society’s annual meeting in Baltimore. Dr. Krumholz and Dr. Aquino presented the pill color preference data in a separate poster at the meeting. The bioequivalence results are expected in 2013.

There’s a fascinating study in today’s Journal of the American Medical Association. It’s a

Photo by flicker member DISCARDEDteenz used under Creative Commons license

meta-analysis of randomized controlled trials comparing antidepressants vs. placebo. And it showed that the placebo effect is so strong in depression that placebos work as well as paroxetine (Paxil) and imipramine (Tofranil) for all patients except those with major depressive disorder that’s classified as “very severe.” Placebo tied active medication for “mild,” “moderate,” and even “severe” depression.

Why didn’t we know this before? The study’s authors explained that there are two reasons. One is that the vast majority of the thousands of clinical trials on depression enroll only patients with very severe depression, even though the vast majority of people taking antidepressants have less severe forms of the disorder.

The second reason is that many studies include what’s called a “placebo washout” period, in which all patients being considered for the trial are given a placebo for a few days up to a week. Those who show more than 20% improvement in their depression are dropped. But removing placebo responders clearly biases the study in favor of finding significant medication effects.

It’s a demonstration that the “gold standard” of medical research–the randomized, double-blind, placebo-controlled trial–can be misleading, especially when we bow to the temptation to generalize results from a highly selected group of test subjects to the wider population.